Cardiorespiratory fitness and brain atrophy in early Alzheimer disease.

OBJECTIVE: To examine the correlation of cardiorespiratory fitness with brain atrophy and cognition in early-stage Alzheimer disease (AD). BACKGROUND: In normal aging physical fitness appears to mitigate functional and structural age-related brain changes. Whether this is observed in AD is not known. METHODS: Subjects without dementia (n = 64) and subjects with early-stage AD (n = 57) had MRI and standard clinical and psychometric evaluations. Peak oxygen consumption (VO(2)(peak)), the standard measure of cardiorespiratory fitness, was assessed during a graded treadmill test. Normalized whole brain volume, a brain atrophy estimate, was determined by MRI. Pearson correlation and linear regression were used to assess fitness in relation to brain volume and cognitive performance. RESULTS: Cardiorespiratory fitness (VO(2)(peak)) was modestly reduced in subjects with AD (34.7 [5.0] mL/kg/min) vs subjects without dementia (38.1 [6.3] mL/kg/min, p = 0.002). In early AD, VO(2)(peak) was associated with whole brain volume (beta = 0.35, p = 0.02) and white matter volume (beta = 0.35, p = 0.04) after controlling for age. Controlling for additional covariates of sex, dementia severity, physical activity, and physical frailty did not attenuate the relationships. VO(2)(peak) was associated with performance on delayed memory and digit symbol in early AD but not after controlling for age. In participants with no dementia, there was no relationship between fitness and brain atrophy. Fitness in participants with no dementia was associated with better global cognitive performance (r = 0.30, p = 0.02) and performance on Trailmaking A and B, Stroop, and delayed logical memory but not after controlling for age. CONCLUSIONS: Increased cardiorespiratory fitness is associated with reduced brain atrophy in Alzheimer disease (AD). Cardiorespiratory fitness may moderate AD-related brain atrophy or a common underlying AD-related process may impact both brain atrophy and cardiorespiratory fitness.

Peripheral insulin and brain structure in early Alzheimer disease.

OBJECTIVE: Accumulating evidence suggests insulin and insulin signaling may be involved in the pathophysiology of Alzheimer disease (AD). The relationship between insulin-mediated glucoregulation and brain structure has not been assessed in individuals with AD. METHODS: Nondemented (Clinical Dementia Rating [CDR] 0, n = 31) and early stage AD (CDR 0.5 and 1, n = 31) participants aged 65 years and older had brain MRI to determine whole brain and hippocampal volume and 3-hour IV glucose tolerance tests to determine glucose and insulin area under the curve (AUC). Linear regression models were used to assess the relationship of insulin and glucose with brain volume, cognition, and dementia severity. RESULTS: In early AD, insulin and glucose AUCs were related to whole brain (insulin beta = 0.66, p < 0.001; glucose beta = 0.45, p < 0.01) and hippocampal volume (insulin beta = 0.42, p < 0.05; glucose beta = 0.46, p < 0.05). These relationships were independent of age, sex, body mass index, body fat, cardiorespiratory fitness, physical activity, cholesterol, and triglycerides. Insulin AUC, but not glucose, was associated with cognitive performance in early AD (beta = 0.40, p = 0.04). Insulin AUC was associated with dementia severity (Pearson r = -0.40, p = 0.03). Glucose and insulin were not related to brain volume or cognitive performance in nondemented individuals. CONCLUSIONS: Increased peripheral insulin is associated with reduced Alzheimer disease (AD)-related brain atrophy, cognitive dysfunction, and dementia severity, suggesting that insulin signaling may play a role in the pathophysiology of AD.

Phonological, semantic, and repetition priming with homophones.

The current study investigated semantic, repetition, and phonological priming using heterographic homonyms (homophones) as stimuli in a lexical decision task. As in previous research, reliable semantic priming and repetition effects were found In addition, the statistical additivity of these two effects was replicated using homophones as stimuli. Using homophones, a reliable phonological priming effect was found when 10-16 intervening trials were used This effect was also statistically independent of semantic priming indicating the independence of the mechanisms responsible for semantic and phonological priming. The magnitude of the phonological priming effect was also significantly less than the magnitude of the repetition effect. This difference in effect magnitude was taken to indicate that the repetition of phonological information is not a primary contributor to the repetition effect.

The relationship between the free concentrations of Ca2+ and Ca2+-calmodulin in intact cells.

Using stably expressed fluorescent indicator proteins, we have determined for the first time the relationship between the free Ca2+ and Ca2+-calmodulin concentrations in intact cells. A similar relationship is obtained when the free Ca2+ concentration is externally buffered or when it is transiently increased in response to a Ca2+-mobilizing agonist. Below a free Ca2+ concentration of 0.2 microM, no Ca2+-calmodulin is detectable. A global maximum free Ca2+-calmodulin concentration of approximately 45 nM is produced when the free Ca2+ concentration exceeds 3 microM, and a half-maximal concentration is produced at a free Ca2+ concentration of 1 microM. Data for fractional saturation of the indicators suggest that the total concentration of calmodulin-binding proteins is approximately 2-fold higher than the total calmodulin concentration. We conclude that high-affinity calmodulin targets (Kd /= 100 nM) occurs only where free Ca2+-calmodulin concentrations can be locally enhanced.